PCI new syllabus based b. pharm 5 th sem anti cancer agents ppt

1. MEDICINAL
CHEMISTRY OF ANTI
CANCER AGENTS
B.pharm 5th sem
PREPARED BY
K.SATTANATHAN M.PHARM
ASST. PROFESSOR
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

2. INTRODCUTION WHAT IS CELL?
April 21 K.SATTANATHAN M.PHARM 2

3. INTRODCUTION
 CELLSARE THE BASIC UNITSTHAT MAKE UPTHE HUMAN
BODY.
 CELLSGROWAND DIVIDETO MAKE NEW CELLSASTHE BODY
NEEDSTHEM .
April 21 K.SATTANATHAN M.PHARM 3

4. INTRODUCTION WHAT IS CANCER ?
April 21 K.SATTANATHAN M.PHARM 4

5. INTRODCUTION
 CANCER IS AN ABNORMAL CELL DIVIDEWITHOUT CONTROL AND
CAN INVADE NEARBYTISSUES.
 THESE ABNORMAL CELLS ARETERMED CANCER CELLS,
MALIGLNANT CELLS ORTUMOR CELLS
 CANCER CELLS CAN ALSO SPREADTO OTHER PARTS OFTHE BODY
THROUGHTHE BLOOD AND LYMPH SYSTEM.
 THIS PROCESS OF CANCER CELLS LEAVING AN AREA ISTERMED
METASTATIC SPREAD OR METASTASIS.
April 21
K.SATTANATHAN M.PHARM
5

6. INTRODUCTION
April 21 K.SATTANATHAN M.PHARM 6

7. INTRODUCTION WHAT ISTUMOR ?
April 21 K.SATTANATHAN M.PHARM 7

8. INTRODCUTION
 Most cancers form a lump called a tumor or a growth. But not all
lumps are cancer.
 Lumps that are not cancer are called benign
 Lumps that are cancer are called malignant
 Some cancers, like leukemia (cancer of the blood), don’t form
tumors.They grow in the blood cells or other cells of the body.
April 21 K.SATTANATHAN M.PHARM 8

9. INTRODUCTION STATISTICAL DATA
April 21 K.SATTANATHAN M.PHARM 9

10. INTRODUCTION
28%
24%
15%
12%
9%
5%
7%
CANCER PATIENTS IN NEW CASES
BREAST CANCER LUNG CANCER PROSTATE CANCER
COLORECTAL CANCER SKIN LEUKEMIA
BLADDER
April 21 K.SATTANATHAN M.PHARM 10

11. INTRODUCTION CELL CYCLE BIOLOGY
April 21 K.SATTANATHAN M.PHARM 11

12. INTRODUCITON
 CANCER IS LEADINGCAUSE OF DEATH INWORLDWIDE . IT
ACCOUNTED FOR 9.6 MILLION DEATH
 LUNG, PROSTATE , CERVICAL, STOMACH, LIVER,COLON,AND
BREAST CANCER CAUSETHE MOST CANCER DEATH EACH
YEAR
April 21 K.SATTANATHAN M.PHARM 12

13. INTRODUCTION
G1
PHASE
S
PHASE
G2
PHASE
M
PHASE
G0
PHASE
April 21 K.SATTANATHAN M.PHARM 13

14. INTRODUCTION
 G1 PHASE OR GAP PHASE INWHICHTHE CELLGROWTH AND
PREPARETO SYNTHESIS DNA
 S PHASE OR SYNTHESIS PHASE INWHICHTHE CELL SYNTHESIS
DNA
 G2 PHASE OR SECONDGAP, PHASE INWHICHTHE CELL
PREPARETO DIVIDEAND
 M PHASE OR MITOSIS PHASE INWHICH CELL DIVISIONOCCURS
 G0 PHASE IS A NON PROLIFERATIVE PHASE
April 21 K.SATTANATHAN M.PHARM 14

15. INTRODUCTION
 TYPES OF CANCER
CARCINOMA
SARCOMA
LEUKEMIA
LYMPHOMA
MYELOMA
MELANOMA
NEUROENDOCRINE TUMOURS
CARCINOID TUMOURS
April 21 K.SATTANATHAN M.PHARM 15

16. INTRODUCTION
 CARCINOMA
 It is the most common form of cancer that affects the epithelial
cells which form the lining of internal organs or the skin
 SARCOMA
 These cancer cells develop in the bones and soft tissues such
as fat tissues, cartilages, blood vessels, lymph and other
supporting tissues of tendons and ligaments.
 The most common form of sarcoma in the bone is
osteosarcoma, and in soft tissues include Kaposi sarcoma,
liposarcoma, malignant fibrous histiocytoma, leiomyosarcoma,
and dermatofibrosarcoma protuberans.
 LEUKAEMIA
Commonly known as blood cancer, leukaemia affects the tissues of
the bone marrow which is responsible for blood production. It is one
of the fatal forms of cancer.
April 21 K.SATTANATHAN M.PHARM 16

17. INTRODUCTION
CAUSES OF CANCER
CANCER CAN BE CAUSED BY MANY
THINGS INCLUDING EXPOSURE TO
CANCER- CAUSING SUBSTANCE,
CERTAIN BEHAVIORS, AGE, AND
INHERITED GENETIC MUTATIONS
April 21 K.SATTANATHAN M.PHARM 17

18. INTRODUCTION
 PHYSICAL CARCINOGEN SUCH AS ULTRAVIOLET AND IONIZING
RADIATION
 CHEMICAL CARCINOGEN SUCH AS ASBESTOS, TOBACCO,
AFLATOXIN,AND ARSENIC
 BIOLOGICAL CARCINOGENS SUCH AS INFECTIONS FROM
CERTAINVIRUSES, BACTERIA OR PARASITES.
April 21 K.SATTANATHAN M.PHARM 18

19. INTRODUCTION
SYMPTOMS OF CANCER
April 21 K.SATTANATHAN M.PHARM 19

20. INTRODUCTION
 UNUSUAL BLEEDING
 PERSISTANT COUGH
 CHANGES IN BOWEL OR BLADDER HABITS
 PERSISTENT LUMP
 A SORETHAT DOES NOT HEAL
 INDIGESTION OR SWALLOWING TROUBLE
 CHANGE IN APPEARANCE OF MOLE OR
WART
April 21 K.SATTANATHAN M.PHARM 20

21. INTRODUCTION DIAGNOSIS OF CANCER
April 21 K.SATTANATHAN M.PHARM 21

22. INTRODUCTION
 MOST CAREGIVERSWILLORDER A COMPLETE BLOOD COUNT ,
ELECTROLYTE LEVELSAND IN SOMECASES,OTHER BLOOD
STUDIES
 IMAGING STUDIESARE COMMONLY USEDTO X-RAYS,CT SCAN
, MRI SCAN AND ULTRA SOUNDAND ENDOSCOPY
April 21 K.SATTANATHAN M.PHARM 22

23. INTRODUCTION
BREAK THROUGH IN CANCER
SCIENCE
April 21 K.SATTANATHAN M.PHARM 23

24. INTRODUCTION
 THE GREEK PHYSICIAN HIPPOCRATES USED IN NAME
CARCINOMA FROM THE GREEK WORK KARCINOS. IT MEANING
CRAB . IT REFERS TO THE SHELL- LIKE SURFACE, LEGLIKE
FILAMENTS, AND SHARP PAIN OFTEN ASSOCIATED WITH
TUMORS
 IN 1968 RESEARCHER DEMONSTRATED THAT WHEN A
TRANSFORMING VIRUS INFECTS A NORMLA CELL, IT INSERTS
OND OF ITS GENES INTOTHE HOST CELLGENOME
 AN ONCOGENE,”SRC” WAS THE FIRST DISCOVERED CANCER
GENE
April 21 K.SATTANATHAN M.PHARM 24

25. INTRODUCTION
April 21 K.SATTANATHAN M.PHARM 25

26. INTRODUCTION THERAPIES OF CANCER
April 21 K.SATTANATHAN M.PHARM 26

27. INTRODUCTION
 SURGERY
 RADIATIONTHERAPY
 CHEMOTHERAPY
 PALLIATIVECARETHERAPY
 IMMUNOTHERAPY
 STEMCELLSTRANSPLANT
 TISSUE BIOPSY
 MAMMOGRAM
April 21 K.SATTANATHAN M.PHARM 27

28. INTRODUCTION  CANCER CHEMOTHERAPY
April 21 K.SATTANATHAN M.PHARM 28

29. INTRODUCTION
 CANCER CHEMOTHERAPY IS THE TREATMENT OF CANCER
USINGANTICANCER DRUGS.
 THESE DRUGS ARE OFTEN USED AS PART OF MULTIMODALITY
THERAPY, THAT IS, ALONG WITH SURGERY AND/OR
RADIOTHERAPY,TOACHIEVE AND MAINTAIN REMISSION
April 21 K.SATTANATHAN M.PHARM 29

30. CLASSIFICATION
OFANTICANCER
AGENTS
ANTI CANCER
AGENTS
ALKYLATING
AGENTS
ANTI
METABOLITE
PLANT
ALKALOIDS
April 21 K.SATTANATHAN M.PHARM 30

31. CLASSIFICATION
OFANTICANCER
AGENTS
ANTI CANCER
AGENTS
ANTI CANCER
ANTIBIOTICS
MISCELLANEOUS HORMONES
April 21 K.SATTANATHAN M.PHARM 31

32. CLASSIFICATION
OFANTI
CANCER
AGENTS
1. ALKYLATING AGENTS
A. NITROGEN MUSTARD Eg: MECHLORETHAMINE, MELPHALAN,
CYCLOPHOSPHAMIDE, CHLORAMBUCIL
B. ETHYLENE AMIDE & METYLENE AMIDE DERIVATIVE Eg:
THIOTEPA, ALTERATAMINE
C. METHYL HYDRAZINE DERIVATIVE Eg: PROCARBAZINE
D. ALKYL SULFONATE Eg: BUSULFAN
E. NITROSOUREA Eg; CARMESTINE ,LOMUSTINE
F. TRIAZENE Eg: TAMOZOLAMIDE
G. PLATINUM COORDINATION Eg: CISPLATIN, CARBO PLATIN,
OXALIPLATIN
April 21 K.SATTANATHAN M.PHARM 32

33. CLASSIFICATION
OFANTICANCER
AGENTS
ANTI METABOLITE
A. FOLIC ACID DERIVATIVES Eg: METHOTREXATE ,
RALTITREXED, PEMETREXED
B. PURINE DERIVATIVES Eg: CLABRIDINE, MERCEPTOPURINE,
AZOTHIOPURINE, PENTOSTATIN, NELARABINE
C. PYRIMIDINE DERIVATIVES EG: FLUROURACIL, CYTARABINE,
FLOXURIDINE, PEMETREXOL, CAPECITABINE, GEMCITABINE
April 21 K.SATTANATHAN M.PHARM 33

34. CLASSIFICATION
OFANTICANCER
AGENTS
PLANT ALKALOID
A. VINCAALKALOID Eg: VINCRISTINE, VINBLASTINE
B. TAXANE Eg: PACLITAXEL, DOCETAXEL
C. EPIPODOPHYLLOTOXIN Eg: ETOPSIDE
D. CAMPTETHECIN Eg: TOPOTECAN
April 21 K.SATTANATHAN M.PHARM 34

35. CLASSIFICATION
OFANTICANCER
AGENTS
ANTI CANCER ANTIBIOTICS
 DACTINOMYCIN, DANURUBICIN, DOXORUBICIN, BLEOMYCIN,
MITOMYCIN, EPIRUBICIN , VALRUBICIN
MISCELLANEOUS
 PIPROBROMAN, HYDROXY UREA , IMITINIB, SORAFENIB, LAPATINIB,
NILOTINIB, BORTEZOMIB, TEMSIROLIMUS
HORMONES
 STEROID HORMONES
- GLUCOCORTICOIDS
- ESTROGEN AND ANTI ESTROGEN
- ANDROGENS AND ANTI ANTROGEN
- PROGESTIN
April 21 K.SATTANATHAN M.PHARM 35

36. CLASSIFICATI
ONOFANTI
CANCER
AGENTS
 ADRENOCORTICOIDS- PREDINOSONE
 PROGESTIN – HYDROXY PROGESTONE, MEDROXY
PROGESTONE
 ESTROGENS – DIETHYLSTILBESTROL, ETHINYL ESTRADIOL,
 ANTI ESTROGENS-TAMOXIFEN,TOREMIFENE
 AROMATASE INHIBITORS – ANASTROZOLE, LETROZOLE,
EXEMESTANE
 ANTI ANDROGEN- FLUTAMIDE,CASODEX
 GnRHANALOGE- LEUPROLIDE
April 21 K.SATTANATHAN M.PHARM 36

37. STRUCTURE
OFANTI
CANCER
AGENTS
MECHLORETHAMINE
 IUPAC NAME :
2-Dichloro-N-methyldiethylamine
hydrochloride
 MELTING POINT : 109-110 C
 SOLUBILITY : VERY SLIGHTLY SOLUBLE
IN WATER
 PKA : 6.43
April 21 K.SATTANATHAN M.PHARM 37

38. STRUCTURE
OFANTI
CANCER
AGENTS
MELPHALAN
 IUPAC NAME : 4-[Bis (2-
chloroethyl) amino]-L-
phenylalanine
 MELTING POINT: 182.5 C
April 21 K.SATTANATHAN M.PHARM 38

39. STRUCTURE
OFANTI
CANCER
AGENTS
CYCLOPHOSPHOAMIDE
 IUPAC NAME: N, N-Bis (2-
chloroethyl) tetrahydro-2H-1, 1,
3, 2-oxazaphosphorin-2-amine-2-
oxide
 soluble in water
 melting point : 106 -113
 Log p 0.8
April 21 K.SATTANATHAN M.PHARM 39

40. STRUCTURE
OFANTI
CANCER
AGENTS
 THIOTEPA
 IUPAC NAME : N, N′, N′′-
Triethylenethio-phosphoramide
 MELTING POINT : 51 IN
CELSIUS
 SOLUBILITY : WATER
April 21 K.SATTANATHAN M.PHARM 40

41. STRUCTURE
OFANTI
CANCER
AGENTS
CIS PLATIN
 IUPAC NAME: cis-
Dichlorodiamine platinum
 Melting point: 270
 Solubility : soluble in water
April 21 K.SATTANATHAN M.PHARM 41

42. STRUCTURE
OFANTI
CANCER
AGENTS
BUSULFAN
 IUPAC NAME: : 1, 4-
Butanediol
dimethanesulphonate
 MELTING POINT: 106 -107
in Celsius
 SOLUBILITY: soluble in
acetone
 LOG P : -0.52
April 21 K.SATTANATHAN M.PHARM 42

43. STRUCTURE
OFANTI
CANCER
AGENTS
 VINCRISTINE
 It is alkaloid obtained from
the plant of vica rosesus
 Family : apocyanaceae
 MELTING POINT: 218
 SOLUBILITY: soluble in water
 pKa: 5.4
April 21 K.SATTANATHAN M.PHARM 43

44. STRUCTURE
OFANTI
CANCER
AGENTS
 VINBLASTINE
 It is alkaloid obtained from
the plant of vica rosesus
 Family : Apocyanaceae
 Melting point: 267 in Celsius
 Solubility : soluble in alchols
 Log p: 3.7
 pKa: 5.4, 7.4
April 21 K.SATTANATHAN M.PHARM 44

45. STRUCTURE
OFANTI
CANCER
AGENTS
 ETOPOSIDE
 BINOMICAL NAME:
PODOPHYLLUM PELTATUM
 RESULTING IN DNA
DAMAGETHROUGH
STRAND BREAKAGE
INDUCED BYTHE
FORMATION OFTERNARY
COMPLEXOF DRUG, DNA
AND ENZYME
April 21 K.SATTANATHAN M.PHARM 45

46. STRUCTURE
OFANTI
CANCER
AGENTS
FLURO URACIL
 IUPAC NAME: 5-Fluoro-2, 4
(1H, 3H)-pyrimidinedione
 Melting point: 283 in Celsius
 Solubility : soluble in water
and methanol
 Log p : -0.89
 pKa: 8. 02
April 21 K.SATTANATHAN M.PHARM 46

47. STRUCTURE
OFANTI
CANCER
AGENTS
MERCEPTOPURINE
 IUPAC NAME o-Mercapto-6-
purine
 Melting point: 313 in Celsius
 Solubility : insoluble in water
April 21 K.SATTANATHAN M.PHARM 47

48. STRUCTURE
OFANTI
CANCER
AGENTS
AZATHIOPRINE
 IUPAC NAME : 6-[1-Methyl-4-
nitromidazole-5 yl] thio] purine
 Melting point: 243.5 in Celsius
 Solubility ; Insoluble in water ,
very slightly soluble in ethanol
 Log p ; 0.1
 PKA 7.8
April 21 K.SATTANATHAN M.PHARM 48

49. STRUCTURE
OFANTI
CANCER
AGENTS
 THIOGUANINE
 IUPAC NAME 2-amino-3,7-
dihydropurine-6-thione
 MELTING POINT:
GREATER THAN 360 IN
CELSISUS
 SOLUBILITY: INSOLUBLE
IN WATER , FREELY
SOLUBLE IN ALKALI
SOLUTION
 LOG p: -0.07
April 21 K.SATTANATHAN M.PHARM 49

50. STRUCTURE
OFANTI
CANCER
AGENTS
 METHOTREXATE
 IUPAC NAME : (2S)-2-[[4-
[(2,4-diaminopteridin-6-
yl)methyl-
methylamino]benzoyl]amino]
pentanedioic acid
 MELTING POINT :195 IN
CELSIUS
 SOLUBILITY : INSOLUBLE
IN WATER
 LOG P: -1.85
 PKA: 4.7
April 21 K.SATTANATHAN M.PHARM 50

51. STRUCTURE
OFANTI
CANCER
AGENTS
 DANURUBICIN
 IUPAC NAME: 5,12-
Naphthacenedione, (8S-cis)-8-
acetyl-10-[(3-amino-2,3,6-
trideoxy)-α-1-
lyxohexanopyranosyl) oxy]-7, 8,
9, 10-tetrahydro-6, 8, 11-
trihydroxy-10-methoxy,
hydrochloride
April 21 K.SATTANATHAN M.PHARM 51

52. STRUCTURE
OFANTI
CANCER
AGENTS
 DOXORUBICIN
 IUPAC NAME: (7S,9S)-7-
[(2R,4S,5S,6S)-4-amino-5-
hydroxy-6-methyloxan-2-
yl]oxy-6,9,11-trihydroxy-9-
(2-hydroxyacetyl)-4-
methoxy-8,10-dihydro-7H-
tetracene-5,12-dione
 MELTING POINT: 230 IN
CELSIUS
 SOLUBILITY : SOLUBLE
IN WATER
 LOG P: 1.27
 PKA : 7.34, 8.46, 9.46
April 21 K.SATTANATHAN M.PHARM 52

53. STRUCTURE
OFANTI
CANCER
AGENTS
 IDARUBICINE
 IUPAC NAME : (7S,9S)-9-
acetyl-7-[(2R,4S,5S,6S)-4-
amino-5-hydroxy-6-
methyloxan-2-yl]oxy-
6,9,11-trihydroxy-8,10-
dihydro-7H-tetracene-5,12-
dione
 LOG P : 0.2
April 21 K.SATTANATHAN M.PHARM 53

54. STRUCTUREOF
ANTICANCER
AGENTS
BLEOMYCIN
April 21 K.SATTANATHAN M.PHARM 54

55. STRUCTURE
OFANTI
CANCER
AGENTS –
bleomycin
 Bleomycin sulfate is a mixture of cyto toxic water soluble basic
glycopeptide antibiotics isolated by fermentation broth of
Streptomyces verticillus
 bleomycin is used as a Squamous cell carcinoma, Hodgkin’s
disease,Testicular and Overian carcinoma, and malignant plueral
effusion.
April 21 K.SATTANATHAN M.PHARM 55

56. STRUCTURE
OFANTI
CANCER
AGENTS
 DACTINO MYCIN
 IUPAC NAME: 2-amino-4,6-
dimethyl-3-oxo-1-N,9-N-
bis[(3R,6S,7R,10S,16S)-
7,11,14-trimethyl-
2,5,9,12,15-pentaoxo-3,10-
di(propan-2-yl)-8-oxa-
1,4,11,14-
tetrazabicyclo[14.3.0]nonad
ecan-6-yl]phenoxazine-1,9-
dicarboxamide
 MELTING POINT : 241. 5- 243
 LOG P1. 6
April 21 K.SATTANATHAN M.PHARM 56

57. STRUCTURE
OFANTI
CANCER
AGENTS –
MITOMYCIN
 MITOMYCIN IS A DISCOVERED IN A METABOLITE OF
STREPTOMYCESCAESPITOSUS
 MITOMYCINS APPAR- ENTLY WERE THE FIRST OF THE USEFUL
BIOREDUCTIVELY ACTIVATED DNA ALKYLATING AGENTS TO BE
DISCOVERED.
 TREATMENT OF DISSEMINATED ADENOCARCI- NOMA OF THE
STOMACH, COLON,OR PANCREAS
 MEDICINAL CHEMISTRY ASPECTS THAT THE PARTICIPATIONOF
THE C-7 SUBSTITUENT IN ACTIVATION BY THIOLS DIFFERS
SIGNIFICANTLY WHEN C-7 BEARS A METHOXYL GROUP (THE
MITOMYCIN A SERIES) COMPARED TO THE ACTIVATION WHEN
C-7 BEARS AN AMINOGROUP (THE MITOMYCINC SERIES)
April 21 K.SATTANATHAN M.PHARM 57

58. STRUCTURE
OFANTI
CANCER
AGENTS –
MITOMYCIN
 MitomycinC undergoes enzymatic reductive activation to produce
reactive species capable of bis alkylation and crosslinking of DNA,
resulting in inhibition of DNA bio synthesis
April 21 K.SATTANATHAN M.PHARM 58

59. SYNTHESIS
OFANTI
TUMOR
AGENTS
SYNTHESIS OF ANTITUMOR AGENTS
April 21 K.SATTANATHAN M.PHARM 59

60. SYNTHESIS
OF
MECHLORETH
AMINE
April 21 K.SATTANATHAN M.PHARM 60

61. SYNTHESIS
OF
MERCEPTOPU
RINE
April 21 K.SATTANATHAN M.PHARM 61

62. SYNTHESIS
OF
METHOTREX
ATE
April 21 K.SATTANATHAN M.PHARM 62

63. MECHANISM
OFANTI
TUMOUR
AGENTS
April 21 K.SATTANATHAN M.PHARM 63
MECHANISM ACTION OF
ALKYLATING AGENTS

64. MECHANISM
OFANTI
TUMOUR
AGENTS
 THE GENERAL MODE OF ACTION OF ALKYLATING
AGENTS CENTRES AROUND THE FORMATION OF AN
ETHYLENEIMONIUM ION INTERMEDIATE, WHICH IS
HIGHLY UNSTABLE AND FORMS COVALENT BONDS
WITH DNA BASES, THE MOST VULNERABLE TO
ATTACK BEING GUANINE.
April 21 K.SATTANATHAN M.PHARM 64

65. MECHANISM
OFANTI
TUMOUR
AGENTS
 THESE DRUGS TYPICALLY POSSESS TWO REACTIVE GROUPS
CHARACTERIZED BY THE PRESENCE OF A LONE PAIR OF
ELECTRONS ON THE NITROGEN ATOM, DONATION OF WHICH
GIVING RISE TO AN UNSTABLE ETHYLENEIMONIUM ION
FOLLOWING LOSS OF A NEGATIVELY CHARGED CHLORIDE
RADICAL.
April 21 K.SATTANATHAN M.PHARM 65

66. MECHANISM
OFANTI
TUMOUR
AGENTS
April 21 K.SATTANATHAN M.PHARM 66
 THE MAJOR SITE OF ALKYLATION WITHIN DNA IS THE N 7
POSITION OF GUANINE, HOWEVER OTHER BASES ARE ALSO
ALKYLATED TO LESSER DEGRESS, INCLUDING N1 AND N3 OF
ADENINE, N3 OF CYTOSINEAND O6 OF GUANINE

67. MECHANISM
OFANTI
TUMOUR
AGENTS
April 21 K.SATTANATHAN M.PHARM 67

68. MECHANISM
OFANTI
TUMOUR
AGENTS
MECHANISM ACTION OF ANTI METABOLITE AGENTS
April 21 K.SATTANATHAN M.PHARM 68

69. MECHANISM
OFANTI
TUMOUR
ANTI
METABOLITE
 ANTI METABOLITE ANTI CANCER AGENTS HAVE A SIMILAR
MOLECULAR STRUCTURE TOSUBSTRATE OF ENZYMES
INVOLVED IN THE SYNTHESIS OF DNA , A PROCESS THAT
EVENTUALLY DISRUPTS DNA STRUCTURE AND
FUNCTIONALITYAND LEADSTOTUMORCELL DEATH.
 THESE DRUGS MAY INTERACTWITHTWO WAYS
 1. STRUCTURALANALOGSOF PRECURSOR
 2. INTERMEDIATEALONGTHE SYNTHETICCHAIN
April 21 K.SATTANATHAN M.PHARM 69

70. MECHANISM
OFANTI
TUMOUR
ANTI
METABOLITE
 FOLIC ACID IS IMPORTANT DNA PRECURSOR WHICH
UNDERGOES REDUCTION TO DIHYDRO FOLATE AND
FURTHER REDUCED TO TETRA HYDRO FOLATE IN
THE PRESENCE OF DIHYDRO FOLATE REDUCATSE
(DHFR) AND NADPH .
 AN ANTI TUMOR AGENT METHOTREXATE MAINLY
TARGETED TO AN ENZYME OF DIHYDRO FOLATE
REDUCTASE
April 21 K.SATTANATHAN M.PHARM 70

71. MECHANISM
OFANTI
TUMOUR
ANTI
METABOLITE
 REDUCED FOLATE ACT AS A CO FACTOR FOR THYMIDYLATE
SYNTHASE , WHICH CATALYSE THE SYNTHESIS OF PYRIMDINE
NUCLEOTIDES BY CONVERTING DEOXYURIDINE MONO
PHOSPHATETO DEOXYTHYMIDINE PHOSPHATE
 FOLATE ANALOGUES INHIBIT THE SYNTHESIS OF BOTH
PURINES AND PYRIMIDINES ALTHOUGH DRUGS WITH IN THIS
CLASS DIFFER IN THEIR RELATIVES SPECIFITIES AS INHIBITOR
OF DHFR ANDTHYMIDINE SYNTHASE FUNCTION
April 21 K.SATTANATHAN M.PHARM 71

72. MECHANISM
OFANTI
TUMOUR
ANTI
METABOLITE
April 21 K.SATTANATHAN M.PHARM 72

73. MECHANISM
OFANTI
TUMOUR
ANTI
METABOLITE
 DACTINOMMYCIN BINDS NON COVALENTLY TO DOUBLE STRANDED DNA
BY PARTIAL INTERCALATION BETWEEN ADJACENT GUANINE CYSTOSINE
BASES RESULTING IN INHIBITONOF DNA FUNCTION
 THE STRUCTURE FEATURE OF DACTINOMYCIN IMPORTANT FOR ITS
MECHANISM OF CYTOTOXICITY IS THE PLANAER PHENOXAZONE RING,
WHICH FACILITATES INTERACTION BETWEEN DNA BASE PAIRS.
 THE PEPTIDE LOOPS ARE LOCATED WITHIN THE MINOR GROOVE AND
PROVIDE FORADDITIONAL INTERACTION
 THE PREFERENCE FOR GPC BASE PAIRS IS THOUGHT TO BE PARTLY
RELATED TO THE FORMATION OF HYDROGEN BOND BETWEEN THE 2
AMINO GROUPS OF GUANIINE AND THE CARBONYL OF THE L-THREONINE
RESIDUES.
April 21 K.SATTANATHAN M.PHARM 73

74. OVERALL
MECHAINSM
OFANTI
TUMOR
AGENT
April 21 K.SATTANATHAN M.PHARM 74

75. April 21 K.SATTANATHAN M.PHARM 75